Familial thyroid dyshormonogenesis

Summary

Disease definition

Familial thyroid dyshormonogenesis is a type of primary congenital hypothyroidism (see this term), a permanent thyroid hormone deficiency that is present from birth, which results from inborn errors of thyroid hormone synthesis.

Epidemiology

Clinical description

Clinical manifestations are those of other forms of congenital hypothyroidism (see this term). In addition to features of hypothyroidism, patients with dyshormonogenesis can present with goiter.

Etiology

Dyshormonogenesis is caused by hereditary defects in the steps of thyroid hormone synthesis and secretion, the majority of which are transmitted in an autosomal recessive manner but at least one condition has autosomal dominant inheritance. The most common defect is that of thyroid peroxidase activity, which leads to total iodide organification defects (TIOD) and can be caused by autosomal dominant mutations in the DUOX2 and DUOX2A genes (15q15.3, 15q15). Less severe defects cause partial iodide organification defects (PIOD) and can include defects in sodium/iodide transport, defective thyroglobulin action or a defect in the enzyme iodotyrosine deiodinase.

Diagnostic methods

In countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up thyroid-stimulating hormone (TSH) or primary TSH test), infants with congenital hypothyroidism are diagnosed after detection by screening tests. However, goiter is rarely seen in babies detected by newborn screening. Diagnosis should be confirmed by elevated serum TSH level and low T4 or free T4 level. TIOD diagnosis is based on high radioactive iodine (RAI) uptake of the thyroid gland followed by more than 90% release after sodium perchlorate administration. Genetic testing can also be used. PIOD is diagnosed with 50-90% release after perchlorate administration (and can be confirmed by genetic testing).

Differential diagnosis

Differential diagnoses include other forms of congenital hypothyroidism (see this term).

Antenatal diagnosis

Genetic counseling and antenatal diagnosis can be offered in families where a genetic defect has been identified.

Management and treatment

Levothyroxine is the treatment of choice (starting dose 10-15mcg/kg/day), with the immediate goal to raise the serum T4 above 130 nmol/L (10 ug/dL) as rapidly as possible; with these doses, serum TSH usually normalizes in 2-4 weeks. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and T4 or free T4 should be measured every 1-2 months in the first 6 months of life, every 3 months between 6 months and 3 years of age, and 4 weeks after any dose change.

Prognosis

The prognosis of infants started on treatment early is excellent, with IQs similar to sibling or classmate controls. Lower neurocognitive outcomes may occur in those infants started at a later age (>30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.

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